Methods and devices for activating brown adipose tissue with targeted substance delivery

ABSTRACT

Methods and devices are provided for activating brown adipose tissue with targeted substance delivery. Generally, the methods and devices can activate BAT to increase thermogenesis, e.g., increase heat production in the patient, which over time can lead to weight loss and/or improved metabolic function. In one embodiment, a chemical configured to stimulate nerves that activate the BAT and/or to stimulate brown adipocytes directly can be delivered to a patient, thereby increasing thermogenesis in the BAT and inducing weight loss and/or improved metabolic function through energy expenditure. The chemical can be delivered to the patient locally and/or systemically to stimulate the nerves and/or the brown adipocytes.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. patent application Ser.No. 13/977,501 entitled “Methods And Devices For Activating BrownAdipose Tissue With Targeted Substance Delivery” filed Jun. 28, 2013,which claims priority to International Application No. PCT/US11/66399entitled “Methods And Devices For Activating Brown Adipose Tissue WithTargeted Substance Delivery” filed Dec. 21, 2011, which claims priorityto U.S. Provisional Patent Application No. 61/427,991 entitled “MethodsAnd Devices For Activating Brown Adipose Tissue With Targeted SubstanceDelivery” filed Dec. 29, 2010, which are hereby incorporated byreference herein in their entireties.

FIELD OF THE INVENTION

The present invention relates to methods and devices for inducing weightloss and/or improved metabolic function, and in particular to methodsand devices for activating brown adipose tissue.

BACKGROUND OF THE INVENTION

Obesity is becoming a growing concern, particularly in the UnitedStates, as the number of people with obesity continues to increase andmore is learned about the negative health effects of obesity. Severeobesity, in which a person is 100 pounds or more over ideal body weight,in particular poses significant risks for severe health problems.Accordingly, a great deal of attention is being focused on treatingobese patients.

Surgical procedures to treat severe obesity have included various formsof gastric and intestinal bypasses (stomach stapling), biliopancreaticdiversion, adjustable gastric banding, vertical banded gastroplasty,gastric plications, and sleeve gastrectomies (removal of all or aportion of the stomach). Such surgical procedures have increasingly beenperformed laparoscopically. Reduced postoperative recovery time,markedly decreased post-operative pain and wound infection, and improvedcosmetic outcome are well established benefits of laparoscopic surgery,derived mainly from the ability of laparoscopic surgeons to perform anoperation utilizing smaller incisions of the body cavity wall. However,such surgical procedures risk a variety of complications during surgery,pose undesirable post-operative consequences such as pain and cosmeticscarring, and often require lengthy periods of patient recovery.Patients with obesity thus rarely seek or accept surgical intervention,with only about 1% of patients with obesity being surgically treated forthis disorder. Furthermore, even if successfully performed and initialweight loss occurs, surgical intervention to treat obesity may notresult in lasting weight loss, thereby indicating a patient's need foradditional, different obesity treatment.

Nonsurgical procedures for treating obesity have also been developed.However, effective therapies for increasing energy expenditure and/oraltering a patient's metabolism, e.g., a basal metabolic rate, leadingto improvements in metabolic outcomes, e.g., weight loss, have focusedon pharmaceutical approaches, which have various technical andphysiological limitations.

It has been recognized in, for example, U.S. Pat. No. 6,645,229 filedDec. 20, 2000 and entitled “Slimming Device,” that brown adipose tissue(BAT) plays a role in the regulation of energy expenditure and thatstimulating BAT can result in patient slimming. BAT activation isregulated by the sympathetic nervous system and other physiological,e.g., hormonal and metabolic, influences. When activated, BAT removesfree fatty acids (FFA) and oxygen from the blood supply for thegeneration of heat. The oxidative phosphorylation cycle that occurs inthe mitochondria of activated BAT is shown in FIGS. 1 and 2.

Accordingly, there is a need for improved methods and devices fortreating obesity and in particular for activating BAT.

SUMMARY OF THE INVENTION

The present invention generally provides methods and devices foractivating brown adipose tissue with targeted substance delivery. In oneembodiment, a medical method is provided that includes positioning adevice in contact with tissue of a patient proximate to a receptor incommunication with at least a portion of a depot of brown adiposetissue, and activating the device to deliver a chemical to the patientto activate the brown adipose tissue and increase energy expenditure ofthe brown adipose tissue. The depot of brown adipose tissue can belocated anywhere, such as in a supraclavicular region of the patient.

The chemical can have a variety of configurations. For example, thechemical can be configured to chemically interact with cellular surfacereceptors of the brown adipose tissue. For another example, the chemicalcan include menthol.

The chemical can be delivered to the patient in a variety of ways. Inone embodiment, the chemical can be continuously delivered to thepatient for a predetermined amount of time, e.g., at least four weeks.The device can be configured to be in continuous direct contact with thetissue of the patient for at least one day with the device continuouslydelivering the chemical to the patient for at least one day.

In one embodiment, the method can include delivering a second chemicalto the patient. The chemical can be configured to respond to the secondchemical when the chemical is exposed to the second chemical, theresponse of the chemical causing activation of the brown adipose tissue.The chemical can be configured to be active in the patient when thechemical is exposed to the second chemical, and can be configured to beinert in the patient when the chemical is not exposed to the secondchemical. Delivering the second chemical to the patient can includealternating at least once between delivering the second chemical to thepatient during a first period of time and not delivering the secondchemical to the patient during a second period of time.

The method can include positioning a second device in contact withtissue of the patient proximate to a receptor in communication with atleast a portion of another depot of brown adipose tissue, and activatingthe second device to deliver a second chemical to the patient toactivate the other depot of brown adipose tissue and increase energyexpenditure of the other depot of brown adipose tissue. The seconddevice can deliver the second chemical to the patient simultaneouslywith the device delivering the chemical to the patient.

The device can be activated in response to a trigger event including atleast one of the patient eating, the patient resting, a thresholdtemperature of the patient, a directional orientation of the patient, achange in the patient's weight, a change in the patient's tissueimpedance, manual activation by the patient or other human, a bloodchemistry change in the patient, and a signal from a controller inelectronic communication with the device. The device can be activated todeliver the chemical to the patient to activate the brown adipose tissuewithout cooling the patient or the brown adipose tissue.

Positioning the device in contact with tissue of the patient proximateto a receptor in communication with at least a portion of a depot ofbrown adipose tissue can include positioning the device proximate to atleast one of a supraclavicular region, a nape of a neck, a scapula, aspinal cord, proximal branches of the sympathetic nervous system thatterminate in BAT depots, a kidney, the brain, and the gut.

The method can vary in any number of ways. For example, the method caninclude targeting the chemical to a nerve innervating the brown adiposetissue to activate the brown adipose tissue. For another example,delivering the chemical to the patient can include applying the chemicalto an exterior surface of skin proximate to the depot of brown adiposetissue. For yet another example, positioning the device in contact withtissue of the patient can include transcutaneously applying the deviceto an exterior skin surface of the patient or subcutaneously positioningat least a portion of the device within the patient. Subcutaneouslypositioning at least a portion of the device within the patient caninclude implanting the device entirely within the patient. For stillanother example, the method can include reducing an amount of thechemical delivered to the patient over a predetermined period of timeuntil a first predetermined threshold event occurs, and subsequentlyincreasing the amount of the chemical delivered to the patient over thepredetermined period until a second predetermined threshold eventoccurs. For another example, the method can include imaging the patientto locate the depot of brown adipose tissue prior to positioning thedevice in contact with tissue of the patient proximate to the depot ofbrown adipose tissue.

For another example, the method can include stopping delivery of thechemical, waiting a predetermined amount of time, and activating thedevice to deliver an additional amount of the chemical to the patient toactivate the depot of brown adipose tissue and increase energyexpenditure of the brown adipose tissue. The stopping, the waiting, andthe activating can be repeated until occurrence of a threshold event.The threshold event can include at least one of a predetermined amountof time and a predetermined physiological effect.

For yet another example, the method can include removing the device fromthe patient, repositioning the device in contact with tissue of thepatient proximate to a receptor in communication with at least a portionof another depot of brown adipose tissue, and activating the deviceproximate to the other depot of brown adipose tissue to deliver thechemical to the patient to activate the other depot of brown adiposetissue and increase energy expenditure of the other depot of brownadipose tissue. The depot of brown adipose tissue can be in asupraclavicular region on one of a left and right side of a sagittalplane of the patient, and the other depot of brown adipose tissue can bein a supraclavicular region on the other of the left and right side ofthe sagittal plane of the patient. The device can be removed andrepositioned after the chemical has been delivered to the depot of brownadipose tissue for a threshold amount of time, e.g., at least sevendays. The device can continuously deliver the chemical to the patientduring the threshold amount of time. In response to a trigger event, thedevice can be removed from contact with tissue of the patient andrepositioned to be in contact with another area of tissue of the patientproximate to another depot of brown adipose tissue. The trigger eventcan include at least one of the patient eating, the patient resting, athreshold temperature of the patient, a directional orientation of thepatient, a change in the patient's weight, a change in the patient'stissue impedance, manual activation by the patient or other human, ablood chemistry change in the patient, and a signal from a controller inelectronic communication with the device.

The device can have a variety of configurations. In one embodiment, thedevice can include a housing configured to be disposed in direct contactwith the tissue of the patient proximate to the receptor incommunication with at least a portion of the depot of brown adiposetissue, and a chemical source coupled to the housing and configured todeliver a chemical to the patient. The housing can include a housing ofa patch attached to the patient. The chemical can be allowed to bedelivered from the chemical source to the depot of brown adipose tissueduring a first period of time, the chemical can be prevented from beingdelivered from the chemical source to the depot of brown adipose tissueduring a second period of time after the first time period, and thechemical can be allowed to be delivered from the chemical source to thedepot of brown adipose tissue during a third period of time after thesecond time period. In one embodiment, the device can include acontroller configured to turn the chemical source on to start thedelivery of the chemical to the patient, turn the chemical source off tostop the delivery of the chemical to the patient, or both. Thecontroller can be configured to be located remotely from the patient andto be in electronic communication with the chemical source. Thecontroller can be configured to be implanted entirely within thepatient.

The chemical source can have a variety of configurations. In oneembodiment, the chemical source can include a time-release pill. Inanother embodiment, the chemical source can be located within thehousing. In yet another embodiment, the chemical source can include areservoir contained within the housing and storing a supply of thechemical. The reservoir can be configured to deliver the chemical sourceto the depot of brown adipose tissue.

In another embodiment, a medical method is provided that includespositioning a device in contact with tissue of a patient proximate to areceptor in communication with at least a portion of a first depot ofbrown adipose tissue, activating the device to deliver a first chemicalto the patient to activate the first depot and increase energyexpenditure of the first depot, delivering the first chemical to thepatient until a first threshold event occurs, when the first thresholdevent occurs, stopping delivery of the first chemical to the patient,delivering a second chemical to the patient to activate a receptor incommunication with at least a portion of a second depot of brown adiposetissue and increase energy expenditure of the second depot, deliveringthe second chemical to the patient until a second threshold eventoccurs, and, when the second threshold event occurs, stopping deliveryof the second chemical.

The first and second chemicals can have a variety of configurations. Inone embodiment, the first and second chemicals are identical. In anotherembodiment, the first chemical can be configured to chemically interactwith cellular surface receptors of the first depot. The second chemicalcan be configured to chemically interact with the cellular surfacereceptors of the first depot. The second chemical can include anactivator configured to cause the first chemical to chemically interactwith the cellular surface receptors of the first depot, and the firstchemical can be inert until the first chemical is exposed to the secondchemical.

The first and second chemical can be delivered to the patient in anynumber of ways. For example, at least one of the first and secondchemicals can be delivered to the patient by injecting the at least oneof the first and second chemicals into a circulatory system of thepatient, thereby allowing the at least one of the first and secondchemicals to circulate within the patient. Injecting the at least one ofthe first and second chemicals into the circulatory system of thepatient can allow the at least one of the first and second chemicals tocirculate within the patient to both of the first and second depots ofbrown adipose tissue.

In one embodiment, the first and second chemicals can be simultaneouslydelivered to the patient. In another embodiment, the first and secondchemicals can be sequentially delivered to the patient such that thepatient receives only one of the first and second chemicals at a time.When the second threshold event occurs, the device in contact withtissue of the patient proximate to the first depot can be activated todeliver the first chemical to the patient to activate the first depotand increase energy expenditure of the first depot.

The first threshold event can include, e.g., passage of a firstpredetermined amount of time, and the second threshold event caninclude, e.g., passage of a second predetermined amount of time. Thefirst and second predetermined amounts of time can vary, such as eachbeing at least about 24 hours or each being at least about seven days.

The first and second depots can have a variety of locations. In oneembodiment, the first depot can be located on one of a left and rightside of a sagittal plane of the patient, and the second depot can belocated on the other of the left and right sides of the sagittal planeof the patient.

The method can have any number of variations. For example, the firstchemical can be targeted to a nerve innervating the first depot of thebrown adipose tissue to activate the first depot of brown adiposetissue. For another example, before delivering the second chemical tothe patient, the device can be repositioned to be in contact with tissueof the patient proximate to the receptor in communication with at leasta portion of the second depot, and the device can be used to deliver thesecond chemical to the patient. For yet another example, a second devicecan be positioned in contact with tissue of the patient proximate to thereceptor in communication with at least a portion of the second depot,and the second device can be used to deliver the second chemical to thepatient.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood from the following detaileddescription taken in conjunction with the accompanying drawings, inwhich:

FIG. 1 is a schematic view of an oxidative phosphorylation cycle thatoccurs in mitochondria within BAT cells;

FIG. 2 is a schematic view of BAT mitochondria showing an oxidativephosphorylation cycle that occurs in the mitochondria;

FIG. 3 is a schematic view of PET-CT images showing the locations of BATdepots in a patient subject to a cold environment and in the patient ina normal, warm environment;

FIG. 4 is a transparent view of a portion of a human neck, chest, andshoulder area with a shaded supraclavicular region; and

FIG. 5 is a front view of a body showing one embodiment of an electricalstimulation device positioned on opposite sides of the body's sagittalplane.

DETAILED DESCRIPTION OF THE INVENTION

Certain exemplary embodiments will now be described to provide anoverall understanding of the principles of the structure, function,manufacture, and use of the devices and methods disclosed herein. One ormore examples of these embodiments are illustrated in the accompanyingdrawings. Those skilled in the art will understand that the devices andmethods specifically described herein and illustrated in theaccompanying drawings are non-limiting exemplary embodiments and thatthe scope of the present invention is defined solely by the claims. Thefeatures illustrated or described in connection with one exemplaryembodiment may be combined with the features of other embodiments. Suchmodifications and variations are intended to be included within thescope of the present invention.

Various exemplary methods and devices are provided for activating brownadipose tissue (BAT). In general, the methods and devices can activateBAT to increase thermogenesis, e.g., increase heat production and energyexpenditure in the patient, which can treat metabolic disorders, such asobesity, diabetes, and hyperlipidemia. Therefore, activating BAT toincrease thermogenesis can, over time, lead to one or more of weightloss, a change in the metabolism of the patient, e.g., increasing thepatient's basal metabolic rate, and improvement of comorbidities inobese or non-obese patients, e.g., Type II diabetes, high bloodpressure, etc. In an exemplary embodiment, a chemical configured tostimulate nerves that activate the BAT and/or to stimulate brownadipocytes directly can be delivered to a patient, thereby increasingthermogenesis in the BAT and inducing weight loss and/or improvingmetabolic function through energy expenditure. As will be appreciated bya person skilled in the art, an obese patient can have a body mass index(BMI) greater than 30 kg/m², and a non-obese patient can have a BMI lessthan 30 kg/m². In this way, weight loss and/or improved metabolicfunction can be induced without performing a major surgical procedure,without relying on cooling of the patient, and without surgicallyaltering a patient's stomach and/or other digestive organs. A chemical,solution, drug, medicant, neutriceutical, or pharmaceutical administeredto patient to activate BAT is generally referred to herein as a“chemical.” As discussed further below, the chemical can be configuredto elicit depolarization of a nerve pathway that ultimately results inactivation of BAT. As also discussed further below, the chemical can bedelivered to the patient locally and/or systemically to stimulate thenerves and/or the brown adipocytes. The chemical can be deliveredlocally to the patient by administering the chemical to a targeted areaof the patient's body, such as directly to a BAT depot, to a regionproximate to a BAT depot, or to a region containing receptors incommunication with BAT that when activated results in the activation ofBAT, such as by injecting the chemical directly into the targeted areaor by positioning a chemical delivery device proximate to the targetedarea. Alternatively or in addition, the chemical can be deliveredsystemically to the patient by introducing the chemical into agastrointestinal tract, subcutaneous tissues, or a circulatory system ofthe patient. In this way, the chemical can be administered to thepatient at any one or more selected body locations and can be allowed tocirculate within the patient. In this way, regardless of where thechemical is delivered to a patient, e.g., at a shoulder area, orally,nasally, etc., the chemical can be circulated throughout the patient toreach and activate a plurality of BAT depots.

Following a surgical procedure to treat obesity such as Roux-en-Ygastric bypass (RYGB), a patient can lose weight due to an increase inenergy expenditure, as demonstrated for example in a rodent model inStylopoulos et al., “Roux-en-Y Gastric Bypass Enhances EnergyExpenditure And Extends Lifespan In Diet-Induced Obese Rats,” Obesity 17(1 Oct. 2009), 1839-47. Additional data from Stylopoulos et al. (notpublished in the previous article or elsewhere as of the filing date ofthe present application) indicates that RYGB is also associated withincreased levels of uncoupling protein 1 (UCP1), which is an uncouplingprotein in mitochondria of BAT, as well as with a significant reductionin the size of fat stores within BAT and an increased volume of BAT. Itthus appears that RYGB causes activation of BAT, although as discussedabove, surgical procedures to treat obesity, such as gastric bypass,risk if not necessarily cause a variety of undesirable results. Devicesand methods to activate BAT without a major surgical procedure like RYGBbut instead by either endogenous or exogenous substance with stimulationto increase energy expenditure are therefore provided. Onecharacteristic of BAT that distinguishes it from white adipose tissue(WAT) stores is the high number of mitochondria in a single BAT cell.This characteristic makes BAT an excellent resource for burning energy.Another distinguishing characteristic of BAT is that when activated,UCP1 is utilized to introduce inefficiency into the process of adenosinetriphosphate (ATP) creation that results in heat generation.Upregulation of UCP1 is therefore a marker of BAT activation.

Activation of brown adipocytes leads to mobilization of fat storeswithin these cells themselves. It also increases transport of FFA intothese cells from the extracellular space and bloodstream. FFAs in theblood are derived primarily from fats metabolized and released fromadipocytes in WAT as well as from ingested fats. Stimulation of thesympathetic nervous system is a major means of physiologicallyactivating BAT. Sympathetic nerve stimulation also induces lipolysis inWAT and release of EFA from WAT into the bloodstream to maintain FFAlevels. In this way, sympathetic stimulation leads ultimately to thetransfer of lipids from WAT to BAT followed by oxidation of these lipidsas part of the heat generating capacity of BAT.

The controlled activation of BAT can be optimized, leading to weightloss and/or improved metabolic function, by reducing the stores oftriglycerides in WAT. A person skilled in the art will appreciate thatexposure to cold temperature leads to the activation of BAT to helpregulate body temperature. This knowledge allows the location of BAT tobe readily assessed using positron emission tomography—computedtomography (PET-CT) imaging. FIG. 3 shows scans of a patient subjectedto a cold environment (left two images) and the same patient scanned ina normal, warm environment (right two images). Shown in black areregions of intense glucose uptake—namely, the brain, the heart, thebladder, and in the cold environment, BAT. However these images show thelocations of BAT depots—namely the nape of the neck, the supraclavicularregion, over the scapula, alongside the spinal cord, and around thekidneys as referenced by, for example, Rothwell et al, “A Role For BrownAdipose Tissue In Diet-Induced Thermogenesis,” Nature, Vol. 281, 6 Sep.1979, and Virtanen et al., “Functional Brown Adipose Tissue in HealthyAdults,” The New England Journal of Medicine, Vol. 360, No. 15, Apr. 9,2009, 1518-1525. Applying cold to BAT and/or otherwise activating BAT asdiscussed herein can thus improve glucose tolerance in a patient, andthereby be effective to treat a metabolic disease such as diabetesindependent of weight loss and regardless of whether the patient isobese or non-obese. For example, in their paper, Bartell et al., “Brownadipose tissue activity controls triglyceride clearance,” NatureMedicine, Vol. 17, February 2011, 200-205, describe exposing mice tocold and detecting improved glucose tolerance after exposure to cold.

A person skilled in the art will appreciate that adult humans havesubstantial BAT depots, as indicated, for example, in J. M. Heaton, “TheDistribution Of Brown Adipose Tissue In The Human,” J Anat., 1972 May,112(Pt 1): 35-39, and W. D. van Marken Lichtenbelt et al,“Cold-Activated Brown Adipose Tissue in Healthy Men,” N. Engl. J. Med.,2009 April, 360, 1500-1508. A person skilled in the art will alsoappreciate that BAT is heavily innervated by the sympathetic nervoussystem, as indicated, for example, in Lever et al., “Demonstration Of ACatecholaminergic Innervation In Human Perirenal Brown Adipose Tissue AtVarious Ages In The Adult,” Anat Rec., 1986 July, 215(3): 251-5, 227-9.Further, “[t]he thin unmyelinated fibers that contain norepinephrine(and not NPY) are those that actually innervate the brown adipocytesthemselves. They form a dense network within the tissue, being incontact with each brown adipocyte (bouton-en-passant), and their releaseof norepinephrine acutely stimulates heat production and chronicallyleads to brown adipose tissue recruitment”. B. Cannon, and J.Nedergaard, “Brown Adipose Tissue: Function And PhysiologicalSignificance,” Physiol Rev., 2004: 84: 277-359.

Nerves innervating BAT can be stimulated to activate UCP1 and henceincrease energy expenditure through heat dissipation throughtranscutaneous and/or direct stimulation of nerves innervating BAT.Transcutaneous and direct stimulation are each discussed below in moredetail.

In some embodiments, transcutaneous and/or direct stimulation of nervesinnervating BAT can be combined with one or more treatments, beforeand/or after transcutaneous and/or direct stimulation of BAT, which canhelp encourage BAT stimulation and/or increase an amount of BAT in apatient. For non-limiting example, a pharmaceutical can be administeredto a patient, a light can be delivered to the patient, a magnetic fieldcan be targeted to a region of the patient, the patient can be cooled,the patient can be heated, a BAT-stimulation procedure can be performedon the patient directed to a BAT depot and/or to a nerve innervatingBAT, the patient can engage in weight loss therapies, and/or a surgicalprocedure can be performed on the patient, such as a procedure to induceweight loss and/or to improve metabolic function, e.g., glucosehomeostatis, lipid metabolism, immune function,inflammation/anti-inflammatory balance, etc. A non-limiting example ofcooling the patient includes applying a cold pack to skin of the patientfor a period of time. The cold pack can be applied to a region of theskin with a high concentration of cold receptors, such as near thewrists, ankles, and/or regions having thermosensitive transient receptorpotential (TRP) channels (e.g., TRPA1, TRPV1, TRPM8, etc.).Alternatively or in addition, the cold pack can be applied to the skinproximate to a BAT depot and/or to nerves innervating a BAT depot.Providing electrical stimulation, e.g., using an implanted electricalstimulation device, such that the BAT depot can be simultaneouslyactivated through a mechanism associated with a lowered body temperatureand electrically stimulated, thereby potentially further encouragingadditive or synergistic activation of the BAT. Exemplary embodiments ofmethods and devices for delivering an electrical signal to activate BATare described in more detail in U.S. Pat. Pub. No. 2011/0270360 filedDec. 29, 2010 entitled “Methods And Devices For Activating Brown AdiposeTissue Using Electrical Energy.” Non-limiting examples of a nervestimulation technique configured to stimulate a nerve innervating BATinclude delivery of a medium to the nerve that induces an actionpotential in the nerve, e.g., electricity, light, mechanicalmanipulation or vibration, a magnetic field, a chemical substance, etc.Non-limiting examples of a BAT-stimulation procedure include inducingdifferentiation of muscle, WAT, preadipocytes, or other cells to BAT,and/or implanting or transplanting BAT cells into a patient.Non-limiting examples of implanting or transplanting BAT cells includeremoving cells from a patient, culturing the removed cells, andreimplanting the cultured cells; transplanting cells from anotherpatient; implanting cells grown from embryonic stem cells, adult stemcells, or other sources; and genetically, pharmacologically, orphysically altering cells to improve cell function. Non-limitingexamples of such weight loss therapies include a prescribed diet andprescribed exercise. Non-limiting examples of such a surgical procedureinclude gastric bypass, biliopancreatic diversion, vertical sleevegastrectomy, adjustable gastric banding, vertical banded gastroplasty,intragastric balloon therapy, gastric plication, Magenstrasse and Mill,small bowel transposition, biliary diversion, vagal nerve stimulation,duodenal endoluminal barrier, and procedures that allow for removal offood from the stomach. Combining one or more treatments, particularly aweight loss therapy or a weight loss surgical procedure which does notactivate BAT, e.g., a procedure other than RYGB, biliopancreaticdiversion (BPD) with or without duodenal switch, or some duodenal orother intestinal barrier (e.g., a prescribed diet and/or exerciseprogram, adjustable gastric banding, vertical banded gastroplasty,sleeve gastrectomy, gastric plication, Magenstrasse and Mill,intragastric balloon therapy, some duodenal or other intestinal barrier,and small bowel transposition, with a means for acute or chronicactivation of BAT such as the nerve stimulation discussed herein, canresult in desirable patient outcomes through a combined approach.

Because BAT activation may lead to an increase in body temperaturelocally, regionally, or systemically, transcutaneous and/or directstimulation of nerves innervating BAT can be combined with one or moreheat dissipation treatments, before and/or after transcutaneous and/ordirect stimulation of BAT. Non-limiting examples of such a heatdissipation treatment include inducing cutaneous/peripheralvasodilation, e.g., local or systemic administration of Alphaantagonists or blockers, direct thermal cooling, etc.

Whether BAT is activated directly and/or transcutaneously, targetanatomical areas for BAT nerve stimulation and/or direct stimulation ofbrown adipocytes using a chemical can include areas proximate to BATdepots, e.g., a supraclavicular region, the nape of the neck, over thescapula, alongside the spinal cord, near proximal branches of thesympathetic nervous system that terminate in BAT depots, around at leastone of the kidneys, the brain (e.g., molecules within the pathway suchas activators of Melanocortin 4 and its associated ligands such as MSHα,etc.), and the gut (e.g., antagonists to CB-1 receptors, agonists ofTRPV1, TRPA1, and TRPM8), and other receptors in the body that whenstimulated result in the activation of BAT (e.g., cold receptors in thewrists and/or ankles, etc.). Any BAT depot can be selected foractivation. For non-limiting example, in one embodiment illustrated inFIG. 4, a device (not shown) can be positioned proximate to an area overa scapula in a supraclavicular region S. Identification of one or moreBAT depots for activation can be determined on an individualized patientbasis by locating BAT depots in a patient by imaging or scanning thepatient using PET-CT imaging, tomography, thermography, or any othertechnique, as will be appreciated by a person skilled in the art.Non-radioactive based imaging techniques can be used to measure changesin blood flow associated with the activation of BAT within a depot. Inone embodiment, a contrast media containing microbes can be used tolocate BAT. The contrast media can be injected into a patient whose BAThas been activated. An energy source such as low frequency ultrasoundcan be applied to the region of interest to cause destruction of bubblesfrom the contrast media. The rate of refill of this space can bequantified. Increased rates of refill can be associated with active BATdepots. In another embodiment, a contrast media containing a fluorescentmedia can be used to locate BAT. The contrast media can be injected intoa patient whose BAT has been activated. A needle based probe can beplaced in the region of interest that is capable of counting the amountof fluorescent contrast that passes the probe. Increased counts per unittime correspond to increased blood flow and can be associated withactivated BAT depots. Because humans can have a relatively small amountof BAT and because it can be difficult to predict where BAT is mostprevalent even near a typical BAT depot such as the nape of the neck,imaging a patient to more accurately pinpoint BAT depots can allow morenerves innervating BAT to be stimulated and with greater precision. Anynumber of BAT depots identified through patient imaging can be markedfor future reference using a permanent or temporary marker. As will beappreciated by a person skilled in the art, any type of marker can beused to mark a BAT depot, e.g., ink applied on and/or below theepidermis, a dye injection, etc. The marker can be configured to only bevisible under special lighting conditions such as an ultraviolet light,e.g., a black light.

Methods of measuring BAT activation can be determined through energyexpenditure involving continuous measurements of heat output (directcalorimetry) or inhaled/exhaled gas exchange (indirect calorimetry) insubjects. The term “energy expenditure,” as used herein, refers to theamount of energy (calories), that a person uses to breathe, circulateblood, digest food, support routine physiological functions and bephysically active. To prevent weight gain, energy intake (caloricintake) must be balanced with energy expenditure.

Measurements of the heat released from a person's body can determine howmuch energy an activity has consumed. In addition, indirect calorimetrycan measure oxygen consumption, carbon dioxide production and/ornitrogen excretion to calculate a ratio that reflects energyexpenditure. A component of energy expenditure can be calculated asbasal energy expenditure, which is the amount of energy required tomaintain the body's normal metabolic activity, i.e. respiration, bodytemperature, etc.

Such energy expenditure or metabolic heat production in a subject can beassessed using several techniques. For measurement of the basalmetabolic rate, the subject must be within its thermal neutral zone,which is the range of environmental temperatures across which thesubject's body temperature can be maintained at its basal metabolicrate. The subject must be in a postabsorptive state, quiescent, insexual repose, and resting but conscious. Since the latter prerequisiteis often difficult to achieve with non-human subjects, the fasting heatproduction is used for animals which are quiet, but not necessarilyresting.

Energy expenditure or metabolic heat production can be detectedexternally by a subject's heat loss pattern. Radiation, through which 40to 60% of heat is lost from a subject, can be readily measured using anycommercially available pyrometer or temperature sensor, since mostradiated heat loss can be displayed in the 5-12 μm wavelength range ofthe electromagnetic spectrum. Direct and indirect calorimetry arefurther methods for assessing energy expenditure. Direct calorimetrymeasures heat loss from a subject directly by placing the subject atrest or exercising in a chamber surrounded by a waterjacket. Heatemitted from the subject raises the temperature of the water. Thedifference in the temperature of water entering and leaving the chamberreflects the subject's energy expenditure. Indirect calorimetry measuresgas exchange and relates it to heat production. Indirect calorimetryinvolves monitoring of the amount of oxygen consumed (or conversely, theamount of carbon dioxide produced), and calculating the amount of energyexpended by the subject, depending on the food substrate being utilized(e.g., fat, carbohydrate or protein).

Metabolic rate can also be measured through the use of doubly labeledwater methods in which the average metabolic rate of an organism ismeasured over time. The use of doubly labeled water methods measures thesubject's carbon dioxide production. Oxygen in body water can be lost incarbon dioxide, excretions and evaporative losses. However, hydrogen canonly be lost through body water loss. Taking advantage of the change inbody water and carbon dioxide production over time can be used tomathematically calculate metabolic rate.

Whether BAT is activated directly and/or transcutaneously, targetcellular areas for BAT nerve stimulation and/or direct stimulation ofbrown adipocytes can include cell surface receptors (e.g., TGR5, β₁AR,β₂AR, β₃AR, etc.), nuclear receptors (e.g., PPARγ, FXR, RXR, etc.),transcription co-activators and co-repressors (e.g., PGC1α, etc.),intracellular molecules (e.g., 2-deiodinase, MAP kinase, etc.), UCP1activators, individual cells and related components (e.g., cell surface,mitochondria, and organelles), transport proteins, PKA activity,perilipin and HSL (phospho PKA substrate), CREBP (cAMP responseelement-binding protein), adenosine monophosphate-activated proteinkinase (AMPK), bile acid receptors (e.g., TGR5, FGF15, FXR, RXR α,etc.), muscarinic receptors, etc.

In the course of treating a patient, BAT nerves and/or brown adipocytescan be stimulated at any one or more BAT depots directly or indirectlyand can be stimulated simultaneously, e.g., two or more BAT depots beingconcurrently stimulated, or stimulated sequentially, e.g., different BATdepots being stimulated at different times. Simultaneous stimulation ofBAT can help encourage more and/or faster energy expenditure. Sequentialstimulation of BAT can help prevent the “burning out” of target nervesand can help stimulate the creation of new BAT cells. Sequential nervestimulation can include stimulating the same BAT depot more than once,with at least one other BAT depot being activated before activating apreviously activated BAT depot. Simultaneous and/or sequentialstimulation can help prevent tachypylaxis.

The chemical, whether transcutaneously or directly delivered, can beconfigured in a variety of ways. A time between start of chemicaldeliveries for a chemical noncontinuously delivered to BAT can includecan be of any regular, predictable duration, e.g., hourly, daily,coordinated around circadian, ultradian, or other cycles of interest,etc., such as about ten minutes, or can be of any irregular,unpredictable duration, e.g., in response to one or more predeterminedtrigger events, as discussed further below. Generally, the chemical canbe configured to chemically interact with cellular surface receptors ofBAT. In an exemplary embodiment, the chemical can include adepolarization agent, such as an activator of a channel causingdepolarization, e.g., potassium, calcium, etc. In another exemplaryembodiment, the chemical can include a hormone-related chemical, e.g., athyroid hormone, Vitamin D, a bile acid, Retinol, etc. In still anotherexemplary embodiment, the chemical can include a Melanocortin receptor 4(MCR4) protein agonist, TRPA1 agonists such as cinnamaldehyde and allylisothiocyanate, TRPV1 agonists such as capsaicin and resiniferatoxin,and oleoylethanolamide (OEA). In another exemplary embodiment, thechemical can include an odiferous agent, e.g., eucalyptus, juniper,grapefruit, menthol, etc. Menthol can include a manufactured syntheticcompound or can be obtained from one or more mint oils such aspeppermint. One exemplary embodiment of menthol that can be delivered toa patient includes Bengay®, available from Johnson & Johnson of NewBrunswick, N.J.

In still another exemplary embodiment, one chemical delivered to apatient can include an activator, and another chemical delivered to thepatient can include an activatable effector (prodrug) configured torespond to the activator. Generally, the activator can be configured toactivate the effector, which can be configured to be inert until theactivator directly contacts, mixes with, or is otherwise applied to theeffector. In other words, the effector can be configured to notappreciably bind with receptors in the patient until activated in aparticular way, e.g., by coming into direct contact with the activator.The response of the effector to the activator can cause activation ofBAT. Exemplary embodiments of an effector include beta adrenergicmolecules configured to bind with G-protein coupled receptors on BATwithout activating the receptors until an activator, e.g., a protease,is applied to the effector.

In an exemplary embodiment, the effector can be activated by alteringits configuration, e.g., changing from an inert molecule to a moleculewith a binding affinity for one or more receptors, so as to bind withreceptors on a brown adipocyte that can activate BAT. Although theeffector can be configured to be permanently changed, the effector canbe configured to be deactivated with a second, different activator suchthat the molecule with a binding affinity changes back to the inertmolecule. In other words, the effector can be configured to be activatedby being exposed to a first activator, e.g., a chemical having a firstcomposition, and to be deactivated by being exposed to a secondchemical, e.g., a chemical having a second, different chemicalcomposition. An effector configured to be permanently changed can allowfor spatial specificity, e.g., for an effector to be delivered aparticular target in the body, such as with a topically applied cream.An effector configured to be intermittently changed can allow forspatial and/or temporal specificity. In another embodiment, the effectorcan be activated by releasing molecules with a binding affinity for oneor more receptors.

The effector and/or the activator can be systemically or locallydelivered to a patient. Any adverse patient side effects of an effectorand/or an activator can be reduced by locally delivering such aneffector and/or activator such that the effector and/or activator arenot circulated throughout the patient. In an exemplary embodiment, theeffector can be systemically delivered to the patient, e.g., deliveredthrough an injection or oral ingestion, such that the effector cancirculate through a circulatory system of the patient. The activator canbe locally delivered to the patient, e.g., targeted to a particularanatomical location having at least one BAT depot, such as a shoulder.In another exemplary embodiment, the activator can be systemicallydelivered to the patient, and the effector can be locally delivered tothe patient.

The activator and the effector can be simultaneously or sequentiallydelivered to the patient. In an exemplary embodiment, the effector canbe administered to a patient prior to delivery of the activator theretosuch that when the activator is delivered to the patient, the activatorcan activate the previously administered effector. One effector can beadministered to a patient such that only one effector is present in thepatient's body, but any number of effectors can be simultaneously orsequentially administered to a patient such that a plurality ofeffectors are simultaneously present in the patient's body. If two ormore effectors are administered to a patient, each of the effectors canbe configured to respond to a different activator, e.g., to differentchemical compositions, which can help avoid “burning out” of targetareas, provide redundancy in case an activator or effector fails to bedelivered, and allow a BAT depot to be continuously stimulated whilehelping to avoid burn-out from a particular chemical.

In one embodiment, the same chemical can be delivered to a particularBAT depot, either continuously or sequentially. In other words, achemical can be continuously delivered to a particular BAT depot duringa first period of time, delivery thereto can stop during a subsequent,second period of time, and then delivery thereto can begin again duringa third period of time, etc. In another embodiment, a first chemical canbe transcutaneously or directly delivered to a particular BAT depot, andthen subsequently, either immediately thereafter or after a passage of aperiod of time, a second, different chemical can be delivered to thesame particular BAT depot. In this way, chances of a BAT depot adaptingto a particular stimulus, e.g., to a specific cell surface receptoragonist, can be reduced, thereby helping to prevent the BAT depot frombecoming less receptive to chemical stimulation.

The chemical can be administered to a patient in any number of ways, aswill be appreciated by a person skilled in the art. In one embodiment, achemical can be administered to a patient by injecting the chemical intothe patient, e.g., using a needle. The chemical can be injected at anyone or more locations, e.g., directly into a BAT depot, into a patient'scirculatory system, subcutaneous tissue, etc. A particular depth of aneedle can be selected to help ensure that the chemical is injected intoa desired target. By injecting the chemical into a circulatory system ofthe patient, the chemical can be administered to the patient at any oneor more selected body locations and can be allowed to circulate withinthe patient.

In another embodiment, a chemical can be administered to a patient bytopically applying the chemical to an exterior surface of a patient'sskin, such as by applying a gel or cream thereto. The chemical can betopically applied at any location on a patient's body that would resultin activation of BAT, but in an exemplary embodiment, the chemical canbe topically applied at a skin surface proximate to a BAT depot. Inanother exemplary embodiment, the chemical can include a TRP agonistconfigured to target receptors in skin such as TRPV1, TRPA1, TRPM8, andthe like. Similar to that discussed above regarding an injectedchemical, a topically applied chemical can be configured to circulatewithin the patient.

In still another embodiment, a chemical can be administered to a patientby administering a pill containing the chemical to the patient. The pillcan be administered to the patient in any way, e.g., swallowing, as willbe appreciated by a person skilled in the art. In an exemplaryembodiment, the pill can be delivered to a patient's gut, e.g., stomachand/or intestine, which can target antagonists to CB-1 receptors thatreside within the gut, affecting the enzyme that metabolizes endogenouscannabinoids (fatty acid amide hydrolase), agonists of TRPV1, TRPA1, andTRPM8, and that lead to activation of BAT. Various exemplary embodimentsof controlling drug delivery to a targeted region of the body using apill are described in more detail in U.S. patent application Ser. No.12/976,648 filed Dec. 22, 2010 entitled “Pill Catchers” and in U.S. Pat.Pub. No. 2009/0018594 filed Oct. 4, 2007 entitled “Methods And DevicesFor Medical Treatment.”

In yet another embodiment, a chemical can be administered to a patientthrough inhalation, e.g., using a nasal spray.

A chemical can be delivered to a patient continuously or intermittently.In an exemplary embodiment, a chemical can be intermittently deliveredto a patient by alternating at least once between delivering thechemical to the patient during a first period of time and not deliveringthe chemical to the patient during a second period of time.

In an exemplary embodiment, a chemical can be continuously delivered toa patient through time-release administration, e.g., via a pill,microsphere, patch, etc., to the patient. The time-release pill ormicrosphere can be configured to constantly release relatively smalldoses of a chemical into the patient. The chemical can be released onany time schedule, e.g., a particular chemical dosage or volume releasedfor one hour every two hours for a total of four one-hour releases. Inan exemplary embodiment, an amount of menthol, e.g., Bengay® ointmentcan be topically applied to a patient's skin for a period of time, e.g.,one hour. Various methods of applying menthol are described in furtherdetail in Tajino K, et al, “Application Of Menthol To The Skin Of WholeTrunk In Mice Induces Autonomic And Behavioral Heat-Gain Responses,” AmJ Physiol Regul Integr Comp Physiol. 2007 November; 293(5):R2128-35,Epub 2007 Aug. 29. One embodiment of a time-release patch includes a 3MCoTran™ Membrane available from 3M of St. Paul, Minn.

Another exemplary embodiment of an intermittent delivery includes achemical time-released, e.g., via a pill, microsphere, patch, etc., suchthat it can be alternately released during a first period of time andnot be released during a second period of time.

Another exemplary embodiment of an intermittent delivery includes apump, e.g., an infusion pump, configured to sporadically release achemical contained in a reservoir. The chemical can be released on aregular schedule, e.g., released for ten seconds every ten minutes, oron an irregular schedule, e.g., in response to a predetermined triggerevent or whenever the pump is manually activated. The reservoir can berefillable and/or replaceable. In one embodiment, the reservoir can berefillable by removing reservoir from the patient, adding an amount ofchemical to the reservoir, and reattaching or reimplanting thereservoir. In another embodiment, the reservoir can be configured to berefillable when implanted within a patient, such as by using a needleinserted through the patient's skin, through a needle-penetrable,self-sealing septum extending across the reservoir, and into thereservoir, as will be appreciated by a person skilled in the art. Thepump and/or the reservoir in communication therewith can be implanted ortransdermal. In one embodiment, a reservoir storing a supply of achemical, e.g., a liquid drug, can be contained within a housing. Thehousing can be configured to be implanted within a patient or to belocated external to a patient, such as by being applied to an externalskin surface of the patient such as with an adhesively-attached patch.Whether implanted within a patient or not, the reservoir can have anelongate delivery tube such as a catheter coupled thereto such that thechemical contained with the reservoir can be released into the catheterand flow through the catheter to a location remote from the reservoir.Various exemplary embodiments of transcutaneous and/or implantable pumpsand reservoirs configured to deliver a fluid to a patient are describedin more detail in U.S. Pat. No. 4,978,338 filed Jun. 20, 1988 entitled“Insulin Infusion Pump,” U.S. Pat. No. 4,498,843 filed Aug. 2, 1982entitled “Implantable Infusion Apparatus,” U.S. Pat. Pub. No.2009/0204131 filed Feb. 12, 2008 entitled “Automatically Adjusting BandSystem With MEMS Pump,” U.S. Pat. Pub. No. 2009/0171375 filed Dec. 27,2007 entitled “Controlling Pressure In Adjustable Restriction Devices.”

Another exemplary embodiment of an intermittent chemical deliveryincludes periodic injections of a chemical into a patient. Theinjections can occur on a regular schedule, e.g., once every week, orirregularly, e.g., when a predetermined trigger event such as eatingoccurs.

A chemical delivered to a BAT depot can be delivered continuously, inpredetermined intervals, in sporadic or random intervals, in response toone or more predetermined trigger events, or in any combination thereof.If the chemical is continuously delivered to the patient, particularcare should be taken to ensure that the chemical delivered to thepatient will not damage the target nerves or tissues. For a chemicaldelivered intermittently, nerve or tissue damage can be reduced, if notentirely prevented, by selecting an on/off ratio in which the chemicalis not delivered, e.g., “off,” for more time than it is delivered, e.g.,“on.” For non-limiting example, a chemical can be delivered to BATintermittently with an on/off ratio of about 1:19, e.g., a chemicaldelivered for 30 seconds every ten minutes (30 seconds on/9.5 minutesoff). The device delivering the chemical can be configured to respond toone or more predetermined trigger events, e.g., events that are sensedby or otherwise signaled to the device. Non-limiting examples of triggerevents include the patient eating, the patient resting (e.g., sleeping),a threshold temperature of the patient (e.g., a temperature in thestimulated BAT depot or a core temperature), a directional orientationof the patient (e.g., recumbent as common when sleeping), a change inthe patient's weight, a change in the patient's tissue impedance, manualactivation by the patient or other human (e.g., via an onboardcontroller, via a wired or wirelessly connected controller, or upon skincontact), a blood chemistry change in the patient (e.g., a hormonalchange), low energy expenditure, menstrual cycles in women, medicationintake (e.g., an appetite suppressant such as topiramate, fenfluramine,etc.), a nutrient change in the patient (e.g., a change in glucose orglucose transporters, amino acids, bile acids, free fatty acids andfatty acid transporters, and their metabolites, etc.), and amanually-generated or automatically-generated signal from a controllerin electronic communication, wired and/or wireless, with the device.Non-limiting examples of nutrients include lipids such as bile acids,cholesterol and its metabolites, aliphatic fatty acids, peptides andproteins, etc. The controller can be internal to the device, be locatedexternal from but locally to device, or be located external and remotelyfrom device. As will be appreciated by a person skilled in the art, thecontroller can be coupled to the device in any way, e.g., hard-wiredthereto, in wireless electronic communication therewith, etc. In someembodiments, multiple devices can be applied a patient, and at least twoof those devices can be configured to deliver a chemical based ondifferent individual trigger events or combinations of trigger events.

Generally, transcutaneous stimulation of BAT can include applying adevice to an exterior skin surface of a patient proximate to a BAT depotand activating the device to deliver a chemical to the BAT depot. Inthis way, the chemical can activate the BAT proximate to the device bystimulating the nerves innervating the BAT and/or by stimulating brownadipocytes directly. As mentioned above, two or more transcutaneousdevices, same or different from one another, can be simultaneouslyapplied to a patient, proximate to the same BAT depot or to differentBAT depots. Although a patient can have two or more transcutaneouslyapplied devices and although the devices can be configured tosimultaneously deliver a chemical to BAT, the devices can be configuredsuch that only one delivers a chemical at a time. As also mentionedabove, a transcutaneous device can be rotated to different BAT depots ofa patient and deliver a chemical to each of the BAT depots. Rotating adevice between two or more different locations on a patient's bodyand/or removing a device from a patient when not in use can help preventnerve or tissue desensitization and/or dysfunction, can help reduce anyadverse effects of a device's attachment to the body, e.g., irritationfrom an adhesive applying a device to skin, and/or can help stimulatecreation or replication of new BAT in multiple locations on a patient'sbody. For non-limiting example, the device can be placed in varyingpositions on the body to modulate the activity of different regions ofBAT. In one embodiment, the device can be worn on one side of the neck,e.g., the left side, for a period of time and then on an opposite sideof the neck, e.g., the right side, for the next time period, etc. Inanother embodiment, the device can be worn on an anterior side of a BATdepot, e.g., front of a left shoulder on one side of the patient'scoronal plane, for a period of time and then on an opposite, posteriorside of the BAT depot, e.g., back of the left shoulder on the oppositeside of the patient's coronal plane, for the next period of time. In yetanother embodiment, illustrated in FIG. 5, a device 10 can be wornproximate to a BAT depot on one of a left and right side of a sagittalplane P in a supraclavicular region of a body 12 for a period of timeand then the device 10 can be worn on the other of the left and rightsides of the sagittal plane P in the supraclavicular region proximate toanother BAT depot for the next period of time. Although the same device10 is shown in FIG. 5 as being sequentially relocated to differenttissue surface or skin positions on the body 12, as discussed herein,one or both of the devices can be implanted and/or two separate devicescan be used with a patient such that a first device is positioned at onelocation and a second device is positioned at a second, differentlocation.

The transcutaneous device used to transcutaneously activate BAT can havea variety of sizes, shapes, and configurations. Generally, the devicecan be configured to deliver a chemical to tissue at predeterminedintervals, in response to a manual trigger by the patient or otherhuman, in response to a predetermined trigger event, or any combinationthereof. A transcutaneous device configured to deliver a chemical, suchas a transdermal patch, can have a shape configured to conform to apatient's anatomy, e.g., to fit around a patient's neck and over thepatient's clavicles, to help minimize, if not eliminate, slippage orunsticking of the patch from the patient's skin. In an exemplaryembodiment, a transcutaneous device can be attached to a patient duringsleep, although a transcutaneous device can be applied to a patient atany time. Various exemplary embodiment of devices configured totransdermally deliver a chemical are described in more detail in U.S.Pat. No. 6,532,386 filed Aug. 30, 1999 entitled “Electrotransort DeviceComprising Blades,” U.S. Pat. No. 6,072,100 filed Jan. 28, 1998 entitled“Extrudable Compositions For Topical Or Transdermal Drug Delivery,” andU.S. Pat. No. 7,300,409 filed Oct. 17, 2005 entitled “Therapy Patch.”

Optionally, a patch or other transdermal device can be attached to apatient using a placement tool. Generally, the placement tool canfacilitate consistent placement of the device on the patient's skinproximate to a targeted area, e.g., a BAT depot. In one embodiment, theplacement tool can be aligned with a bony landmark of the patient, e.g.,connecting medial and lateral heads of clavicle and/or acromion of thescapula, such that after alignment thereto, the targeted area can berepeatedly consistently identified via the placement tool. Bonylandmarks can be identified in any way, such as by imaging the patientprior to application of the device, as discussed above. The placementtool can be a standalone instrument, or it can be built into the device,e.g., the device and/or adhesive attaching the device to the patientincluding one or more grid marks, numbers, letters, or other measurementmarkings.

Various exemplary embodiments of transcutaneous devices configured tostimulate nerves are described in more detail in U.S. Patent PublicationNo. 2009/0132018 filed Nov. 16, 2007 and entitled “Nerve StimulationPatches And Methods For Stimulating Selected Nerves,” U.S. PatentPublication No. 2008/0147146 filed Dec. 19, 2006 and entitled “ElectrodePatch And Method For Neurostimulation,” U.S. Patent Publication No.2005/0277998 filed Jun. 7, 2005 and entitled “System And Method ForNerve Stimulation,” U.S. Patent Publication No. 2006/0195153 filed Jan.31, 2006 and entitled “System And Method For Selectively StimulatingDifferent Body Parts,” U.S. Patent Publication No. 2007/0185541 filedAug. 2, 2006 and entitled “Conductive Mesh For Neurostimulation,” U.S.Patent Publication No. 2006/0195146 filed Jan. 31, 2006 and entitled“System And Method For Selectively Stimulating Different Body Parts,”U.S. Patent Publication No. 2008/0132962 filed Dec. 1, 2006 and entitled“System And Method For Affecting Gastric Functions,” U.S. PatentPublication No. 2008/0147146 filed Dec. 19, 2006 and entitled “ElectrodePatch And Method For Neurostimulation,” U.S. Patent Publication No.2009/0157149 filed Dec. 14, 2007 and entitled “Dermatome StimulationDevices And Methods,” U.S. Patent Publication No. 2009/0149918 filedDec. 6, 2007 and entitled “Implantable Antenna,” U.S. Patent PublicationNo. 2009/0132018 filed Nov. 16, 2007 and entitled “Nerve StimulationPatches And Methods For Stimulating Selected Nerves,” U.S. patentapplication Ser. No. 12/317,193 filed Dec. 19, 2008 and entitled“Optimizing The Stimulus Current In A Surface Based Stimulation Device,”U.S. patent application Ser. No. 12/317,194 filed Dec. 19, 2008 andentitled “Optimizing Stimulation Therapy Of An External StimulatingDevice Based On Firing Of Action Potential In Target Nerve,” U.S. patentapplication Ser. No. 12/407,840 filed Mar. 20, 2009 and entitled“Self-Locating, Multiple Application, And Multiple Location MedicalPatch Systems And Methods Therefor,” U.S. patent application Ser. No.12/605,409 filed Oct. 26, 2009 and entitled “Offset Electrodes.”

In an exemplary embodiment, the transcutaneous device can include achemical stimulation patch configured to be applied to an external skinsurface and to deliver a chemical to tissue below the skin surface,e.g., to underlying BAT. The chemical can be delivered any depth belowthe skin surface, such as up to about 2 cm below the skin surface, e.g.,at a maximum penetration depth in a range of about 1 to 2 cm. The patchcan be configured to deliver a chemical from an on-board chemical sourceand/or to deliver a chemical received by the patch from a chemicalsource in communication with the patch, e.g., through a delivery tubesuch as a catheter extending between the patch and the chemical source.The device can be wireless and be powered by an on-board and/or externalsource, e.g., inductive power transmission. The patch can be attached tothe skin in any way, as will be appreciated by a person skilled in theart. Non-limiting examples of patch application include using a skinadhesive locally (e.g., on patch rim), using a skin adhesive globally(e.g., on skin-contacting surfaces of the patch), using an overlyingsupport (e.g., gauze with taped edges), using an adherent frame allowinginterchangeability (e.g., a brace or an article of clothing), beingsubdermally placed with wireless connectivity (e.g., Bluetooth), andusing any combination thereof. The device can include receiver circuitryconfigured to interact with a controller in electronic communicationwith a chemical source, e.g., a reservoir or supply, of the device suchthat the controller can control at least some functions of the chemicalrelease mechanism, e.g., on/off status of the chemical and adjustment ofparameters such as release timing and volume of chemical released, etc.In an exemplary embodiment, a chemical stimulation patch can include aplurality of reservoirs, each of which can be the same as or differentfrom any one or more of the other reservoirs. The reservoirs can each beconfigured to contain a different chemical configured to be delivered tothe patient.

In use, and as mentioned above, a chemical stimulation patch can be worncontinuously or intermittently as needed. The patch can be placedproximate to a BAT depot, such as over the left supraclavicular regionof the patient's back, for a predetermined amount of time, e.g., twelvehours, one day, less than one week, seven days (one week), one month(four weeks), etc., and can continuously deliver a chemical to the BAT.As mentioned above, the BAT depot can be identified by imaging thepatient prior to application of the patch proximate to the BAT depot.Seven days is likely the longest period an adhesive can be made to stickto the skin of a patient without modification and can thus be apreferable predetermined amount of time for patches applied to skin withan adhesive. After the predetermined amount of time, the patch can beremoved by a medical professional or the patient, and the same patch, ormore preferably a new patch, can be placed, e.g., on the rightsupraclavicular region of the patient's back for another predeterminedamount of time, which can be the same as or different from thepredetermined amount of time as the first patch applied to the patient.This process can be repeated for the duration of the treatment, whichcan be days, weeks, months, or years. In some embodiments, the processcan be repeated until occurrence of at least one threshold event, e.g.,a predetermined amount of time, a predetermined physiological effectsuch as a predetermined amount of weight lost by the patient, etc. Ifthe same patch is relocated from a first region, e.g., the leftsupraclavicular region, to a second region, right supraclavicularregion, the patch can be reconditioned after removal from the firstregion and prior to placement at the second region. Reconditioning caninclude any one or more actions, as will be appreciated by a personskilled in the art, such as replacing one or more patch components,e.g., a battery, an adhesive, etc.; cleaning the patch; etc.

In one embodiment of intermittent chemical delivery using pump, apatient can wear an infusion style pump storing a supply of a chemicalconfigured to target a cellular surface of a BAT depot, e.g., a betaadrenergic receptor agonist such as norepinephrine. A deliverymechanism, e.g., a needle, can be coupled to the pump to directlydeliver the chemical into a vicinity of the BAT depot. The pump can beconfigured to start pumping a predetermined clinically relevant amountof the chemical through the needle upon occurrence of a predeterminedtrigger event, e.g., when the patient begins eating a meal. In oneembodiment, the patient eating can be determined through a detection ofheart rate variability, as discussed in more detail in U.S. patentapplication Ser. No. 12/980,695 filed Dec. 29, 2010 and entitled“Obesity Therapy And Heart Rate Variability” and U.S. patent applicationSer. No. 12/980,710 filed Dec. 29, 2010 and entitled “Obesity TherapyAnd Heart Rate Variability.” The pump can be configured to quickly rampup and then slowly ramp down delivery of the chemical over apredetermined period of time, e.g., thirty minutes. Such intermittentchemical delivery can be particularly effective if the patientpreviously underwent a surgical procedure to treat obesity that does notactivate energy expenditure, such as a laparoscopic adjustable gastricbanding procedure.

In another embodiment of intermittent chemical delivery using a pump, apatient can wear an infusion style pump storing a supply of a chemicalconfigured to target bile acid receptors, e.g., agonists configured tobind with TGR5 receptors on BAT. A delivery mechanism can be coupled tothe pump to deliver the chemical into a circulatory system of thepatient, similar to delivery of insulin to a diabetic patient, as willbe appreciated by a person skilled in the art. The pump can beconfigured to start pumping a predetermined clinically relevant amountof the chemical at a prescribed, constant rate through the needle uponoccurrence of a first predetermined trigger event, e.g., when thepatient begins eating a meal. In one embodiment, the patient eating canbe detected by a glucose monitor, such as by using one or more readingsmeasured by the glucose monitor to determine satisfaction of apre-programmed algorithm, e.g., when the patient's glucose level exceedsa predetermined threshold value or when the patient's glucose levelincreases or decreases a predetermined amount over a predeterminedperiod of time. The chemical can be continuously delivered to thepatient until occurrence of a second predetermined trigger event, suchas passage of a predetermined amount of time, at which time the pump canstop pumping the chemical to the patient. The first and second triggerevents can be the same as or different from each other. Suchintermittent chemical delivery can be particularly effective asstandalone therapy.

In one embodiment of continuous chemical delivery using pump, a patientcan wear an infusion style pump storing a supply of an MC4 receptoragonist configured to target sympathetic nerves ultimately innervatingBAT. A delivery mechanism, e.g., a needle, can be coupled to the pump todirectly deliver the chemical into a vicinity of the sympathetic nervesinnervating BAT. Patient side effects of the chemical can be reduced byreleasing the chemical into the patient at a site with receptors for thechemical and at a site along the sympathetic chain innervating the BATdepot of interest that is as close as possible to the BAT depot. Thepump can be configured to continuously pump a predetermined clinicallyrelevant amount of the chemical through the needle to maintain asubstantially consistent level of BAT activation when the patient is atrest. The pump can start continuously pumping when a first predeterminedtrigger event occurs, e.g., the pump wirelessly receiving an electronicstart signal or the pump being manually button or switch activated bythe patient. Upon occurrence of a second predetermined trigger event,e.g., when the patient begins eating a meal, the pump can be configuredto increase an amount of chemical being delivered to the patient. Theincreased amount can be continuously delivered to the patient untiloccurrence of a third predetermined trigger event, such as passage of apredetermined amount of time, at which time the pump can resume pumpingthe previous predetermined clinically relevant amount of the chemical tothe patient. Any of the first, second, and third trigger events can bethe same as or different from any of the other trigger events. Suchcontinuous chemical delivery can be particularly effective if thepatient is on a medically prescribed diet and exercise program.

To more accurately simulate a weight loss surgery and/or invasivemetabolic disorder treatment that has a continuous or chronic effect ona patient for an extended period of time, the patch can be placed on apatient and continuously or chronically deliver a chemical thereto foran extended, and preferably predetermined, amount of time. In anexemplary embodiment, the predetermined amount of time can be at leastfour weeks. The chemical can be delivered to same BAT depot for thepredetermined amount of time, or two or more different BAT depots can bestimulated throughout the predetermined amount of time, e.g., left andright supraclavicular regions being stimulated for alternate periods ofseven days to total one month of predetermined time. Continued orchronic nerve stimulation to activate BAT can increase BAT energyexpenditure over time and potentially induce more or faster weight lossand/or metabolism change than periodic or intermittent nervestimulation. The chemical can be the same or can vary during the amountof time such that the chemical is continuously and chronically appliedto the patient to provide 24/7 treatment mimicking the 24/7 consequencesof surgery. The chemical can vary by e.g., by being delivered atdifferent volumes or dosages, by first delivering a first chemical andthen delivering a second, different chemical, etc. The continuous amountof time the patient is stimulated with a chemical can be a total amountof continuous activation of any one BAT depot (e.g., activation of asingle BAT depot), sequential activation of two or more BAT depots,simultaneous activation of two or more BAT depots, or any combinationthereof. A total amount of time of sequential activation of differentBAT depots can be considered as one extended amount of time despitedifferent areas of BAT activation because activation of one BAT depotmay cause the brain to signal for BAT activation in other BAT depots.

Generally, direct activation of BAT can include implanting a devicebelow the skin surface proximate to a BAT depot, e.g., within a BATdepot, and activating the device to deliver a chemical to the nervesinnervating the BAT depot and/or to brown adipocytes directly. BATitself is densely innervated, with each brown adipocyte being associatedwith its own nerve ending, which suggests that stimulating the BATdirectly can target many if not all brown adipocytes and depolarize thenerves, leading to activation of BAT. The sympathetic nerves thatinnervate BAT can be accessed directly through standard surgicaltechniques, as will be appreciated by a person skilled in the art. Thedevice can be implanted on a nerve or placed at or near a nerve cell'sbody or perikaryon, dendrites, telodendria, synapse, on myelin shelth,node of Ranvier, nucleus of Schwann, or other glial cell to stimulatethe nerve. While implanting such a device can require a surgicalprocedure, such implantation is typically relatively short, outpatient,and with greatly reduced risks from longer and more complicated surgicalprocedures such as gastric bypass. In an exemplary embodiment, astimulation device with at least one chemical source can be at leastpartially implanted in the patient, and more preferably entirely withinthe patient. A person skilled in the art will appreciate that any numberof chemical sources, e.g., one or more each delivering a chemical sameor different from any of the other chemical sources, can be at leastpartially implanted in the patient. The chemical source can be implantedin a location sufficiently close to the nerves innervating the BAT sothat when activated, the chemical released from the chemical source issufficiently transferred to adjacent nerves, causing these nerves todepolarize. As mentioned above, the device can include receivercircuitry configured to interact with a controller in electroniccommunication with the chemical source such that the controller cancontrol at least some functions of the chemical source, e.g., on/offstatus of the light source, switching between multiple chemical sourcesincluded in the device, and adjustment of parameters such as dosage,etc.

Various exemplary embodiments of devices configured to directly apply asignal to stimulate nerves are described in more detail in U.S. PatentPublication No. 2005/0177067 filed Jan. 26, 2005 and entitled “SystemAnd Method For Urodynamic Evaluation Utilizing Micro-ElectronicMechanical System,” U.S. Patent Publication No. 2008/0139875 filed Dec.7, 2006 and entitled “System And Method For Urodynamic EvaluationUtilizing Micro Electro-Mechanical System Technology,” U.S. PatentPublication No. 2009/0093858 filed Oct. 3, 2007 and entitled“Implantable Pulse Generators And Methods For Selective NerveStimulation,” U.S. Patent Publication No. 2010/0249677 filed Mar. 26,2010 and entitled “Piezoelectric Stimulation Device,” U.S. PatentPublication No. 2005/0288740 filed Jun. 24, 2004 and entitled, “LowFrequency Transcutaneous Telemetry To Implanted Medical Device,” U.S.Pat. No. 7,599,743 filed Jun. 24, 2004 and entitled “Low FrequencyTranscutaneous Energy Transfer To Implanted Medical Device,” U.S. Pat.No. 7,599,744 filed Jun. 24, 2004 and entitled “Transcutaneous EnergyTransfer Primary Coil With A High Aspect Ferrite Core,” U.S. Pat. No.7,191,007 filed Jun. 24, 2004 and entitled “Spatially Decoupled TwinSecondary Coils For Optimizing Transcutaneous Energy Transfer (TET)Power Transfer Characteristics,” and European Patent Publication No.377695 published as International Patent Publication No. WO1989011701published Nov. 30, 2004 and entitled “Interrogation And Remote ControlDevice.”

In use, at least one chemical source of an implantable stimulationdevice can be placed in the area of a BAT depot. The chemical source canbe in electronic communication with a device external to the patient'sskin to adjust characteristics such as release volume, release timing,etc. The external device can be positioned near the patient's skin,e.g., using a belt, a necklace, a shirt or other clothing item,furniture or furnishings such as a chair or a pillow, or can be adistance away from the patient's skin, such as a source locatedelsewhere in the same room or the same building as the patient. Thechemical stimulation device can include circuitry configured to controlan activation distance, e.g., how close to a power source the chemicalstimulation device must be to be powered on and/or begin delivering achemical to the patient. Correspondingly, the external device caninclude a transmitter configured to transmit a signal to the chemicalstimulation device's circuitry. If implanted, the device can include aninternal power source, e.g., a battery, a capacitor, stimulatingelectrodes, a kinetic energy source such as magnets positioned withinwired coils configured to generate energy within the coils when shakenor otherwise moved, etc. In one embodiment, a battery can include aflexible battery, such as a Flexion battery available from Solicore,Inc. of Lakeland, Fla. In another embodiment, a battery can include aninjectable nanomaterial battery. The power source can be configured tobe recharged by transcutaneous means, e.g., through transcutaneousenergy transfer (TET) or inductive coupling coil, and/or can beconfigured to provide power for an extended period of time, e.g., monthsor years, regardless of how long the power source is intended to providepower to the device. In some embodiments, a power source can beconfigured to provide power for less than an extended period of time,e.g., about 7 days, such as if a battery is replaceable or rechargeableand/or if device real estate can be conserved using a smaller, lowerpower battery.

The controller, and/or any other portion of the device or externaldevice, as will be appreciated by a person skilled in the art, can beconfigured to measure and record one or more physical signals relatingto the activation of BAT. For non-limiting example, the physical signalscan include voltage, current, impedance, temperature, time, moisture,salinity, pH, concentration of hormones or other chemicals, etc. Therecorded physical signals can be presented to the patient's physicianfor evaluation of system performance and efficacy of brown adiposeactivation. Also, the recorded physical signals can be used in aclosed-loop feedback configuration to allow the device, e.g., thecontroller, to dynamically adjust the chemical settings used fortreatment.

The devices disclosed herein can be designed to be disposed of after asingle use, or they can be designed to be used multiple times. In eithercase, however, the device can be reconditioned for reuse after at leastone use. Reconditioning can include any combination of the steps ofdisassembly of the device, followed by cleaning or replacement ofparticular pieces, and subsequent reassembly. In particular, the devicecan be disassembled, and any number of the particular pieces or parts ofthe device can be selectively replaced or removed in any combination.Upon cleaning and/or replacement of particular parts, the device can bereassembled for subsequent use either at a reconditioning facility, orby a surgical team immediately prior to a surgical procedure. Thoseskilled in the art will appreciate that reconditioning of a device canutilize a variety of techniques for disassembly, cleaning/replacement,and reassembly. Use of such techniques, and the resulting reconditioneddevice, are all within the scope of the present application.

Preferably, the invention described herein will be processed before use.First, a new or used instrument is obtained and if necessary cleaned.The instrument can then be sterilized. In one sterilization technique,the instrument is placed in a closed and sealed container, such as aplastic or TYVEK bag. The container and instrument are then placed in afield of radiation that can penetrate the container, such as gammaradiation, x-rays, or high-energy electrons. The radiation killsbacteria on the instrument and in the container. The sterilizedinstrument can then be stored in the sterile container. The sealedcontainer keeps the instrument sterile until it is opened in the medicalfacility.

It is preferred that device is sterilized. This can be done by anynumber of ways known to those skilled in the art including beta or gammaradiation, ethylene oxide, steam, and a liquid bath (e.g., cold soak).An exemplary embodiment of sterilizing a device including internalcircuitry is described in more detail in U.S. Patent Publication No.2009/0202387 filed Feb. 8, 2008 and entitled “System And Method OfSterilizing An Implantable Medical Device.”

One skilled in the art will appreciate further features and advantagesof the invention based on the above-described embodiments. Accordingly,the invention is not to be limited by what has been particularly shownand described, except as indicated by the appended claims. Allpublications and references cited herein are expressly incorporatedherein by reference in their entirety.

What is claimed is:
 1. A medical device, comprising: a pump configured to be applied to an exterior skin surface of a patient at a depot of brown adipose tissue and in communication with a receptor in communication with at least a portion of the depot of brown adipose tissue, wherein the pump has an on-board supply of a chemical, and the pump applied to the exterior skin surface delivers the chemical to the patient to activate the brown adipose tissue and increase energy expenditure of the brown adipose tissue, wherein the delivered chemical is configured to chemically interact with cellular surface receptors of the brown adipose tissue, and the chemical comprises one of a depolarization agent, a hormone-related chemical, an odiferous agent, a Melanocortin receptor 4 (MCR4) protein agonist, a TRPA1 agonist, and a TRPV1 agonist.
 2. The device of claim 1, wherein the pump has a reservoir containing the on-board supply of the chemical.
 3. The device of claim 1, wherein the pump has an on-board controller configured to control the delivery of the chemical based on a predetermined delivery plan.
 4. The device of claim 3, wherein the predetermined delivery plan includes continuous release of the chemical from the pump for a predetermined amount of time.
 5. The device of claim 4, wherein the predetermined amount of time is in a range of twelve hours to four weeks.
 6. The device of claim 3, wherein the predetermined delivery plan includes the controller causing a start of the delivery of the chemical in response to a trigger event, wherein the trigger event includes at least one of the patient eating, the patient resting, a threshold temperature of the patient, a directional orientation of the patient, a change in the patient's weight, a change in the patient's tissue impedance, manual activation by the patient or other human, and a blood chemistry change in the patient.
 7. A medical device, comprising: a patch configured to be applied to an exterior skin surface of a patient at a depot of brown adipose tissue and in communication with a receptor in communication with at least a portion of the depot of brown adipose tissue, wherein the patch applied to the exterior skin surface delivers a chemical to the patient to activate the brown adipose tissue and increase energy expenditure of the brown adipose tissue, wherein the delivered chemical is configured to chemically interact with cellular surface receptors of the brown adipose tissue, and the chemical comprises one of a depolarization agent, a hormone-related chemical, an odiferous agent, a Melanocortin receptor 4 (MCR4) protein agonist, a TRPA1 agonist, and a TRPV1 agonist and wherein the patch has an on-board supply of the chemical that is delivered to the patient or the chemical is received by the patch from a chemical source in communication with the patch that is delivered to the patient.
 8. The device of claim 7, wherein the patch has a reservoir containing the on-board supply of the chemical.
 9. The device of claim 7, wherein the patch has an on-board controller configured to control the delivery of the chemical based on a predetermined delivery plan.
 10. The device of claim 9, wherein the predetermined delivery plan includes continuous release of the chemical from the patch for a predetermined amount of time.
 11. The device of claim 10, wherein the predetermined amount of time is in a range of twelve hours to four weeks.
 12. The device of claim 10, wherein the predetermined amount of time is seven days or less.
 13. The device of claim 9, wherein the predetermined delivery plan includes the controller causing a start of the delivery of the chemical in response to a trigger event, wherein the trigger event includes at least one of the patient eating, the patient resting, a threshold temperature of the patient, a directional orientation of the patient, a change in the patient's weight, a change in the patient's tissue impedance, manual activation by the patient or other human, and a blood chemistry change in the patient. 